A number of cancers are, at present, incurable. For others, chemotherapy is only partially effective and a significant proportion of patients relapse following treatment. Some haematological malignancies are treatable by hematopoietic stem cell transplantation (HSCT), but fewer than 30% of patients requiring HSCT have a suitable donor and are the requisite age.
Natural Killer (NK) cells are a subset of peripheral blood lymphocytes which can spontaneously lyse certain tumour cells. The use of NK cells in adoptive tumour immunotherapy has been proposed, and there has been interest in the in vitro or ex vivo stimulation of NK cells to increase their capacity to lyse tumour cells.
The discovery of interleukin-2 (IL-2) and its role in NK-cell activation in the 1980's led to considerable interest in the use of lymphokine-activated killer (LAK) cells in tumour immunotherapy. The results of these trials were, however, largely disappointing. In a study investigating the effect of administering autologous LAK cells to patients along with IL-2, less than 20% of patients responded (Rosenburg et al (1987) N. Engl. J. Med. 316: 889-897). In studies using daily IL-2 administrations to cancer patients along with chemotherapy and autologous HCT, it was shown that, although IL-2 significantly expanded the number of circulating MK cells in vivo, the cells are not maximally cytotoxic according to an in vitro assay (Miller et al (1997) Biol. Blood Marrow Transplant. 3: 34-44).
NK cells are now known to be controlled by both positive and negative cytolytic signals. A number of molecules which mediate NK cell inhibition have been cloned over the past ten years and their ligands are almost exclusively Class I MHC molecules. Some of these receptors (“KIRs”) are specific for determinants shared by certain class I alleles, and each KIR is expressed by a subset of NK cells. Therefore, in the NK repertoire, some NK cells recognise, and are blocked by, specific class I alleles. NK cells have a limited view of class I polymorphism but cells can be responsible for alloreactions when the mismatched target cells do not express the class I alleles which block every NK cell in the repertoire (the “missing-self” hypothesis). Thus allogeneic target cells which lack at least one of the class I allele groups expressed by the donor cells will not find the inhibitory class I ligand on a subset of donor NK cells and their lytic pathway will be activated.
It has thus been suggested that autologous NK cells may be suppressed by the physiologic response resulting from NK cell recognition of “self” MHC molecules.
It has also been suggested that the greater the degree of KIR mismatch with tumour MHC (i.e. KIR ligand) the greater tumour kill (Ruggeri et al (2002) Science 295:2097-2100). In view of the shortcomings of autologous NK cell therapy (thought to be due to a lack of NK cell inhibitory receptor mismatching with autologous tumour cells) the use of allogeneic NK cell infusions has been suggested as an alternative (Miller et al (2005) Blood in press, but pre-published on-line on Jan. 4, 2005).
Miller et al (2005, as above) administered IL-2 activated allogeneic haploidentical NK cells to patients with metastatic melanoma, metastatic renal cell carcinoma, refractory Hodgkin's disease or poor prognosis AML. Importantly, their results demonstrate that the NK cells can persist and expand in vivo. The cells induced complete hematologic remission in five of the 19 poor prognosis AML patients, but no activity against the other tumours. In the group which achieved remission, patients are stratified into those with predicted graft versus host alloreactivity using the KIR ligand mismatch strategy. The results showed remission was much more likely in those patients which are KIR ligand mismatched.
Non-specifically activated NK cells may therefore have an application against a subset of tumours, but the donor cells must be allogeneic and much more likely to be effective if they are HLA mismatched. A disadvantage associated with using mismatched NK cells is that they may target and reject normal (e.g. host) hematopoeitic cells (Yu et al (1996) Immunity 4:67-76).
There is thus a need for alternative immunotherapy for cancer which is effective against “NK resistant” tumours but which spares normal hematopoietic cells.